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Why Was Zantac Taken Off the Market?
Zantac (ranitidine) was taken off the market because the drug contains
unacceptable levels of N-Nitrosodimethylamine (NDMA), which is a substance
known to cause cancer. Testing of ranitidine drugs showed levels of NDMA
above the FDA’s acceptable daily intake limit of 96 nanograms (ng)
per day. For example, testing from Connecticut-based online pharmacy Valisure
detected NDMA in excess of 3,000,000 ng per tablet when analyzing ranitidine products.
Valisure tests medications for consistency and quality issues. During testing,
the company
discovered extremely high levels of NDMA “in every lot tested, across multiple manufacturers and dosage forms
of the drug ranitidine.”
Valisure’s finding was consistent with studies from Stanford University
and elsewhere, which found that NDMA in Zantac was likely due to the “inherent
instability” of the ranitidine molecule.
“There’s no acceptable cancer risk for a drug like this,”
said David Light, CEO of Valisure.
Valisure reported its findings to the FDA in June of 2019. Three months
later, the company filed a citizen’s petition urging the FDA to
issue a Zantac recall and suspend all sales:
“Combined with other data from Valisure and the scientific works
of Stanford University and others, the evidence presented shows this instability
and the resulting NDMA occurs in the conditions representative of those
in the human body and builds a compelling case for ranitidine being a
likely human carcinogen.”
On Jan. 2, 2020, research laboratory Emery Pharma filed a citizen’s
petition of its own noting that ranitidine is a time and temperature-sensitive
pharmaceutical product that develops into NDMA when exposed to heat. In
a press release, Emery Pharma noted:
“Exposure to high temperatures is a common occurrence during transportation
and storage, and is of specific concern to ranitidine as there currently
are no requirements for the drug to be shipped in temperature-controlled
conditions and/or stored under refrigeration.”
Ranitidine is a very unstable molecule. On one side, you have the N (Nitroso). On the
other side, you have the DMA (Dimethylamine). When the molecule is exposed
to heat, various biological processes in the stomach, and enzymatic reactions
throughout the body, it shears apart and reconstitutes as NDMA. But the
formation of NDMA is not limited to the reaction in human stomach. Ranitidine
can turn into NDMA in the pill bottle itself. In fact, our Zantac lawsuits
allege that the drug manufacturers for decades had this problem where
ranitidine turned yellow in storage. If it’s yellow, that’s
NDMA. They claim they had no idea why this was the case, but our lawsuits
say otherwise—they knew.” –
Zantac Attorney R. Brent Wisner
What is NDMA in Zantac?
N-Nitrosodimethylamine (NDMA) is a water-soluble organic (containing the element carbon) chemical and
appears as a yellow liquid with little or no obvious taste or odor. NDMA
was once used to make rocket fuel, but today is made only for research
purposes. It can also be produced as a byproduct of manufacturing processes.
Humans can be exposed to NDMA in relatively small amounts through various
products, including tobacco, foods (cured meat, fish, cheese, beer), shampoos,
cleansers, and pesticides.
NDMA is carcinogenic even in minimal doses. The FDA’s acceptable
daily intake of NDMA is 96 nanograms (ng), or 96 billionths of a gram.
Studies show that NDMA exposure as little as
179 ng per 100 grams per day is associated with elevated cancer risks.
The International Agency for Cancer Research (IARC), the most recognized
cancer research institution in the world, studied over 200 research papers
on NDMA and the NDMA cancer risk. IARC placed the chemical in the “Group
2A” category, meaning substances that are “probably carcinogenic
to humans.” The agency found that NDMA is “carcinogenic in
all animal species tested” and noted that the metabolism of NDMA
by humans and animals is similar.
NDMA caused malignant tumor growth in several organs, in multiple species,
via numerous routes of exposure (oral, inhalation, subcutaneous (under
the skin), injections), with dose-response relationships appearing in
several studies. Scientists are also gaining detailed knowledge of the
body's biochemical mechanisms to repair NDMA DNA damage and how those
mechanisms play a role in the progression towards cancer.
The FDA, Environmental Protection Agency (EPA), and World Health Organization
(WHO) all classify as a substance capable of causing cancer.
Zantac Recall Update
The following companies issued voluntary Zantac recall announcements, citing safety concerns:
- American Health Packaging
- Amneal Pharmaceuticals
- Aurobindo Pharma USA
- Apotex Corp. (this includes over-the-counter ranitidine tablets 75 mg and
150 mg, labeled by Walgreens, Walmart, and Rite-Aid)
- Appco Pharma
- Denton Pharma (dba Northwind Pharmaceuticals)
- Reddy’s Laboratories (this includes Zantac over-the-counter OTC medicines
labeled by retailers such as Walgreens, Walmart, CVS, Target, and Kroger)
- GlaxoSmithKline (GSK)
- Glenmark Pharmaceuticals
- Golden State Medical Supply
- Lannett Company
- Novitium Pharma
- Perrigo Company
- Precision Dose
- Sandoz
- Sanofi
On April 1, 2020, the FDA issued a market withdrawal request of all Zantac
(ranitidine) products, effective immediately. The FDA announcement noted
that agency studies on Zantac showed “risk to public health.”
As such, the agency said ranitidine products “will not be available
for new or existing prescriptions or OTC use in the U.S.”
To stay updated on Zantac (ranitidine) recall announcements, we advise
you to consult the
FDA’s Recalls, Market Withdrawals, & Safety Alerts page. The FDA alerts consumers with the recall reason and lists Zantac recall
lot numbers, if applicable.
Did the FDA Issue a Zantac Recall in 2019?
Despite evidence that Zantac can cause cancer, the U.S. Food and Drug Administration
(FDA) did not immediately issue a Zantac recall in 2019. The agency warned
consumers that testing of the popular heartburn medication Zantac (generic
ranitidine) revealed a known cancer-causing chemical, N-nitrosodimethylamine
(NDMA) at more than 3,000 times the legal daily intake limit.
While the FDA was reluctant to issue a Zantac recall in 2019, retail outlets
like Walgreens, Walmart, Rite Aid, CVS and others pulled the popular medication
from shelves. Generic drug makers like Sandoz (a division of Novartis),
GSK, and Apotex also issued generic Zantac recalls in 2019; and nearly
two dozen countries stopped or restricted sales of the popular medication.
The FDA issued a market withdrawal for Zantac in 2020. A market withdrawal
is different than a recall.
Per the FDA, here is the difference between a recall and a market withdrawal:
Market withdrawal: Involves a minor violation that would not be subject to legal action
by the FDA.
Recall: The correction or removal of a marketed product that the FDA considers
to be in violation of the laws it administers.
2018 NDMA Recall
In 2018, some companies issued recalls after the discovery of high levels
of NDMA in multiple generic forms of the blood pressure drug valsartan.
The levels of NDMA in these products, however, paled in comparison to
that of Zantac.
The 2018 recalls
were reportedly linked to NDMA that formed during manufacturing after active ingredient suppliers
in India and China sold components of the medication to generic drug makers.
Government officials have not commented on how NDMA ended up in the drugs.
Zantac Lawyers Call for FDA Ranitidine Recall
The Zantac cancer lawyers at Wisner Baum believe the FDA’s decision
to issue a market withdrawal for Zantac is a necessary step toward protecting
people from a dangerous drug. However, more can and should be done. Our
firm has been calling for a Zantac recall since the summer of 2019 because
there is no level of NDMA that is safe.
Zantac 360 with Famotidine on the Market Following Ranitidine Recall
In response to the Zantac recall announcements and the FDA’s market
withdrawal for ranitidine, Sanofi announced a
new Zantac product in 2021 called Zantac 360. Zantac 360 is made with famotidine as the active ingredient instead of
ranitidine. With two different active ingredients, Zantac 360 is not the
same as the original Zantac.
Many people may recognize famotidine, as it is the same active ingredient
used in another popular OTC heartburn drug, Pepcid AC. While both famotidine
and ranitidine are in the same class of drugs (H2 blockers), famotidine
is considered a safe ranitidine replacement because it does not contain
NDMA at high levels.
Does Zantac Cause Cancer?
Yes, Zantac can cause cancer. The ranitidine molecule produces high levels
of N-Nitrosodimethylamine (NDMA) when the drug is used as directed. The
U.S. Food and Drug Administration (FDA), the Environmental Protection
Agency (EPA), and the World Health Organization (WHO) classify NDMA as
a cancer-causing chemical. The ranitidine molecule contains both a nitrite
and a dimethylamine (DMA) group. These combine to form NDMA.
Numerous studies have found that the NDMA in Zantac causes bladder cancer,
stomach cancer, pancreatic cancer, and other forms of cancer. Below we
highlight some of the most important research on Zantac.
2019 Valisure Study: How Zantac (Ranitidine) Produces NDMA
In 2019, Valisure conducted batch testing for Zantac (ranitidine) using
FDA-recommended protocols. Valisure found NDMA levels as high as 3,267,968
ng (nanograms) per Zantac tablet, more than 34,000 times higher than the
FDA limit of 96 ng or .096 mcg (micrograms).
Wondering if the increased heat of the testing process may have contributed
to these results, Valisure decided to test ranitidine under conditions
that simulated those found in the stomach (simulated gastric fluid with
sodium nitrite). NDMA levels, while not as high, were still extraordinary,
ranging from 23,600 ng to 304,500 ng, over 3,100 times the FDA’s
“safe” limit.
“Valisure’s testing reveals NDMA levels so high that the nitroso
for NDMA likely comes from no other source than the ranitidine molecule
itself.” [Nitroso refers to an atomic grouping of nitrogen and oxygen,
such as found in the nitrite group of NDMA.]
—
Valisure Citizen Petition on Ranitidine, September 9, 2019
Valisure also points to a third mechanism that could lead to NDMA production
after Zantac is ingested – an enzyme, dimethylarginine dimethylaminohydrolase
(DDAH), that can react with ranitidine to “liberate” DMA from
ranitidine, making it available to combine with nitrite from the ranitidine
molecule, nitrite circulating in the body, or “other potential pathways
particularly in weak acidic conditions such as that in the kidney or bladder.”
This mechanism, according to Valisure, could generate millions of nanograms
of NDMA throughout the body.
2021 Valisure Study on Zantac (Ranitidine)
The 2021
Valisure Zantac study analyzed NDMA production “under simulated physiologic gastric states.”
What does this mean exactly? Researchers conducted the study by mimicking
the human stomach ingesting a Zantac tablet across a broad range of pH
concentrations, ranitidine concentrations, and nitrite concentrations.
The study used FDA-recommended protocols for determining nitrosamines
in ranitidine tablets.
The study found that Zantac “may be a significant source of NDMA
under a range of physiologically relevant conditions.” Under numerous
conditions meant to simulate the human stomach, Zantac NDMA levels increased
with increasing nitrite levels and decreasing pH levels
up to three orders of magnitude beyond established limits. The authors cautioned, “these data support recent regulatory actions
to limit ranitidine availability.”
Study on Zantac Published in
Cancers
Cancers published a study on Zantac in December of 2020. Researchers looked at data from the FDA’s Adverse
Events Reporting System (FAERS), searching adverse event reports of cancer
stemming from primary and secondary use of proton pump inhibitors (PPIs)
and H2 antagonists, the group of drugs to which Zantac belongs.
The study found elevated incidences of esophageal cancer, pharyngeal cancer,
liver cancer, and pancreatic cancer, and stomach cancer, among others. The
Cancers study provides “support for the assertion that NDMA contaminated
ranitidine is associated with the occurrence of gastrointestinal cancer.
This assertion was bolstered by an abundance of evidence demonstrating
that NDMA exposure is associated with an increased risk of cancer in humans
as well as animals.”
This research is similar to
data from a 2000 study, which investigated the association between prescription ranitidine use
and specific cancers. In the 2000 study, researchers found a statistically
significant
2.4-fold increased risk for stomach cancer and esophageal cancer.
Sloan Kettering Study Finds Association Between Ranitidine and Cancer
Researchers from the Sloan Kettering Cancer Center conducted the study,
‘Ranitidine use, N-Nitrosodimethylamine (NDMA) production and variations
in cancer diagnoses’. The study used similar methods to the 2021 Valisure study above.
The Sloan Kettering study analyzed ranitidine NDMA production under various
simulated gastric conditions. Researchers also conducted an epidemiologic
analysis to evaluate potential associations between ranitidine and several
forms of cancer.
According to the authors, Zantac produces increasing amounts of NDMA over
time (up to, and likely beyond four hours) and with increasing sodium
nitrite concentrations.
The study found positive associations for several cancers, including bladder cancer.
Epidemiological Studies of Zantac and Cancer
Very few epidemiological studies of patients taking Zantac have been conducted.
In a study conducted by the National Cancer Institute, adult male health
professionals with peptic ulcers were followed for 14 years (1986 –
2000). The subjects of the study were asked if they used either Tagamet
or Zantac as a treatment. The authors of the study reported that use of
either drug was associated with an increased risk of bladder cancer, though
the increase fell short of statistical significance.
Other Zantac Studies
A true Zantac cancer study in humans—where humans are deliberately
given Zantac to ingest to observe the results—has not been conducted
and never will, as it would be unethical. However, a 1983 study of ranitidine
in rodents found that it produced several “genotoxic effects,”
including DNA fragmentation in the liver and gastric mucosa (the mucous
membrane that lines the stomach). Significantly, studies of Tagamet (cimetidine),
another antacid in Zantac’s class (H2 blockers), did not show DNA damage.
Genetic damage is known to be at the root of all cancers. A 2013 meta-analysis
of studies that examined the relationship between various acid-suppressing
drugs and gastric cancer concluded that that “acid suppressive drugs
are associated with an increased risk of gastric cancer.”
These studies support three important points underlying the danger posed
by Zantac:
- NDMA is carcinogenic in humans in exceedingly small amounts.
- Levels of NDMA produced by Zantac are extremely high.
- The problem with Zantac is not an “impurity” in the drug, but
rather the design of the drug itself and how that design makes Zantac
itself a carcinogen.
NDMA has not been directly tested in humans. The cancer risk is too high.
However, we know from years of research that humans are regularly exposed
to NDMA via many foods and beverages. This has provided a means of testing
NDMA’s carcinogenic potential—and by extension the carcinogenicity
of Zantac—in humans indirectly.
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